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Use of Neurotransmitter Precursors forTreatment of Depressionby Stephen Meyers, MS
AbstractInsufficient activity of the neurotransmitters serotonin and norepinephrine is a centralelement of the model of depression most widely held by neurobiologists today. In thelate 1970s and 1980s, numerous studies were performed in which depressed patientswere treated with the serotonin precursors L-tryptophan and 5-hydroxytryptophan (5-HTP), and the dopamine and norepinephrine precursors tyrosine and L-phenylalanine.This article briefly reviews the published research on the efficacy of neurotransmitterprecursors in treating depression, highlights the findings of studies, and discussesissues regarding the interpretation of those findings. The nature of the studies makesit difficult to draw firm conclusions regarding the efficacy of neurotransmitter precursorsfor treating depression. While there is evidence that precursor loading may be oftherapeutic value, particularly for the serotonin precursors 5-HTP and tryptophan, morestudies of suitable design and size might lead to more conclusive results. However, theevidence suggests neurotransmitter precursors can be helpful in patients with mild ormoderate depression.(Altern Med Rev 2000;5(1):64-71.)
Introduction
Insufficient activity of the neurotransmitters serotonin and norepinephrine is a central
element of the model of depression most widely held by neurobiologists today.1 Nearly all ofthe drugs used to treat depression appear to enhance neurotransmission in one or both of thesesystems. In fact, understanding of the mechanism of action of antidepressant drugs in part gaverise to the model of depression.
The synthesis of most neurotransmitters is controlled within the brain. For some neu-
rotransmitters, the amount of biochemical precursors present in the brain can influence theirrate of synthesis. During the 1970s, researchers established a body of evidence indicating in-gestion of dietary precursors of certain neurotransmitters could increase their levels in the brain.2This research suggested precursors of norepinephrine and serotonin might be useful in treatingdepression. In the late 1970s and 1980s, numerous researchers studied the use of the serotoninprecursors L-tryptophan and 5-hydroxytryptophan (5-HTP), and the norepinephrine precursorstyrosine and phenylalanine in depressed patients.
Interest in neurotransmitter precursors was partly a function of the shortcomings of
anti-depressant medications (particularly in terms of side-effects) available prior to Prozac andother selective serotonin re-uptake inhibitor drugs (SSRIs). It was hoped dietary precursors ofkey neurotransmitters might provide a more easily tolerated way of treating depression.
Stephen Meyers, MS; Staff Scientist, Lawrence B erkeley National Laboratory, B erkeley, C A, and a writer in the fields of
health and nutrition. Email: spmeyers@lbl.gov.
Page 64 Alternative Medicine Review ◆ Volume 5 Number 1 ◆ 2000
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Why Neurotransmitter Precursors
be balanced by adaptations within the system.Might be Helpful in Treating
beneficial symptom-relieving effect of antide-
Depression
pressant drugs suggests late-developing fac-
tors may be more relevant to these drugs’ clini-
ness of neurotransmitter precursors builds
cal efficacy than their acute effect (inhibiting
upon the idea that depression is a result of an
re-uptake of neurotransmitters). Imipramine (a
inadequate amount or insufficient activity of
tricyclic antidepressant) can block neurotrans-
one or more neurotransmitters. Within limits,
mitter re-uptake in a matter of hours, but it
availability of the necessary precursors deter-
takes several weeks for patients to begin to feel
mines the amount of neurotransmitter synthe-
less depressed. This time lag posed a challenge
sized. For example, serotonin production in the
to the notion that the primary cause of depres-
human brain can be increased two-fold by oral
sion was related to a reduced level of neu-
appears to result in increased neurotransmit-
vestigated long-term adaptive changes pro-
ter synthesis, it is less clear whether it leads to
duced by antidepressant drugs on norepineph-
augmentation of neurotransmitter release. An
rine and serotonin systems.6 In addition, al-
animal study found acute administration of L-
though most current antidepressant drugs are
tryptophan decreased the firing rate of seroto-
known to act on norepinephrine and serotonin
nin neurons,4 which might tend to counteract
systems, other factors appear to be involved
increased synthesis. However, results from
in the mechanism of action of antidepressants.
other animal studies suggest L-tryptophan ad-
ministration can enhance serotonin release
intracellular second messengers, and modula-
under some circumstances, and the same may
tion of gene expression may play a role in the
be true in humans.5 Administration of 5-HTP
mechanism of action of antidepressant drugs.7,8
has been associated with a significant increasein cerebrospinal fluid levels of 5-
Research on the Efficacy of
hydroxyindolacetic acid, the primary metabo-lite of serotonin, suggesting 5-HTP leads to
Neurotransmitter Precursors forTreating DepressionIssues in Evaluating the Research
not been answered—is whether increased neu-
rotransmitter release leads to ongoing stimu-
lation of neurotransmitter activity; i.e., the
the scientific literature on antidepressant treat-
strength of signaling. The latter depends not
ments difficult. One is the quality and dura-
only on the amount of neurotransmitter re-
tion of response to a given treatment. Response
leased by the presynaptic neuron, but also on
in terms of a reduction in the level of symp-
how long neurotransmitters remain in the syn-
toms on a rating scale (“improvement”) is not
aptic cleft, and on factors which influence fir-
the same as remission from illness. The latter
ing of the postsynaptic neuron. Neurotransmit-
requires a longer time frame to evaluate than
ter systems are characterized by feedback
the one-to-two-month treatment period most
mechanisms that help maintain equilibrium
common in clinical studies, but is ultimately
with respect to neurotransmitter activity. Thus,
more important. Reduction in symptoms over
changed conditions in the short run, such as
the course of a study does not necessarily lead
increased synthesis of a neurotransmitter, can
Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000 Page 65
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Figure 1. Serotonin BiosynthesisSerotonin Precursors:5-HTP andTryptophan
Therapeutic use of 5-HTP bypasses the con-
version of L-tryptophan into 5-HTP by the
general classes. In an open study, a treatment
enzyme tryptophan hydroxylase, which is the
is given to a group of patients and their re-
rate-limiting step in the synthesis of serotonin
sponse is measured; a hypothetical contrast of
(see Figure 1). 5-HTP easily crosses the blood-
the response to the treatment compared to that
brain barrier, and unlike L-tryptophan, does
seen with a known drug is possible. The sec-
not require a transport molecule to enter the
ond class contrasts the experimental treatment
central nervous system. These factors might
with a drug of established efficacy. The third
account for the inconsistent results in studies
compares a treatment with placebo, sometimes
using L-tryptophan in the treatment of depres-
using a standard drug as a third arm of the
a number of studies with 5-HTP in the 1970s
treatment is not considered effective without
and early 1980s. Their first study found re-
a placebo control. Placebo response rates vary
duced depressive symptoms in 60 percent of
widely across patient groups; it may be as high
as 65 percent, even in a group with major de-
pression.10 Thus, if an open study finds that a
ment.12 A double-blind study with four groups
particular treatment results in improvement of
of 10 patients found 5-HTP (200 mg/day) was
symptoms, it is difficult to judge how much of
more effective than placebo and almost as ef-
the effect was due to the treatment. Even if an
fective as clomipramine (a tricyclic antidepres-
experimental treatment appears comparable to
sant).13 In seven open studies with a total of
a standard drug in terms of response, it may
350 patients, 55 percent of the patients were
be that a placebo would have done as well as
considered to be responders to 5-HTP.14 Over-
either treatment over the course of the study.
all, it was found to be effective in five and in-effective in two of those studies. In seven con-trolled studies with a total of 78 patients, a
Page 66 Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000
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positive response was noted in 60 percent of
tranylcypromine, 15 improved.20 The authors
patients. In five of these studies, 5-HTP was
felt 5-HTP was not an effective alternative in
found to be effective. The scientists concluded,
patients who had not previously responded to
“there are strong indications that 5-HTP is of
the therapeutic efficacy of 5-HTP was found
conducted in Japan in the 1970s. In a large
to be equal to traditional antidepressants.21 Best
open trial, 100 patients were given 50-300 mg/
results were obtained among patients with an
day.15 Significant improvement was observed
anxious depressive syndrome and in patients
in 69 percent of the patients, and no signifi-
cant side-effects were reported. The response
rate in most of the patients was less than two
100 mg three times per day with fluvoxamine
weeks, which is interesting, as most antide-
(an SSRI used for depression and obsessive-
pressant drugs take two weeks to a month to
compulsive disorder) 50 mg three times per
show benefit. In a 1975 open study, 24 patients
day. In a double-blind, multicenter study, 36
hospitalized for depression were given 5-HTP.
subjects were evaluated over six weeks using
After two weeks of treatment, marked ame-
four different diagnostic tools. Both treatment
lioration of depressive symptoms was observed
groups showed significant and nearly equal
in seven patients (29%).16 In another Japanese
reductions in depression beginning at week
study, 5-HTP (50-100 mg three times per day)
two and continuing through week six. By week
was administered to 59 patients with mixed
six, the two groups had about an equal num-
types of depression; unipolar, bipolar, and
ber of patients showing 50 percent improve-
other subcategories, most with moderate-to-
ment in the Hamilton Rating Scale for Depres-
severe depression. Marked improvement was
noted in 13 patients (22%) and moderate im-
provement in 27 patients (46%). Again, all
that most, if not all, of the subjects had been
responders to 5-HTP therapy noticed improve-
diagnosed with major depression. One double-
ments within two weeks.17 Yet another open
blind study compared L-tryptophan with ami-
study administered 5-HTP to 18 patients and
triptyline (a tricyclic antidepressant) over a
diagnosed with mild or moderate depression.
Based on scores on the Hamilton Depression
in 1977 compared 5-HTP (in combination with
Scale and a global rating of depression, L-tryp-
tophan at a dose of 3 g per day was more ef-
inhibitor—to supposedly inhibit conversion of
fective than placebo, as effective as amitrip-
5-HTP outside the CNS) to imipramine in 30
tyline, and produced significantly fewer side-
patients. It found equal efficacy between the
two treatments.19 A 1985 British study assessed
the efficacy of 5-HTP among patients suffering
above indicate a therapeutic benefit from
serotonin precursors, reviews by others have
responders to several neurotransmitter re-
been more cautious. In a review published in
uptake inhibitors. 5-HTP or tranylcypromine
was given during four weeks in a crossover
reviewed did not provide adequate evidence
for an antidepressant effect of 5-HTP. They
responded, whereas of 26 patients treated with
also felt L-tryptophan without concomitant
Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000 Page 67
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Figure 2. Biosynthesis of Catecholamines
significant difference with a high degree of
Norepinephrine Precursors:Tyrosine and Phenylalanine
nephrine, and L-phenylalanine is the directprecursor of tyrosine. Tyrosine and phenyla-
lanine are also precursors of dopamine, anotherneurotransmitter which may play a role in de-
there appears to be less scope for increasingnorepinephrine synthesis with precursor load-
ing than is the case for serotonin. Under nor-mal conditions in the rat brain, tyrosine hy-
droxylase, the rate-limiting enzyme on thepathway from tyrosine to norepinephrine, isabout 75-percent saturated with tyrosine.5
the use of norepinephrine precursors for treat-
antidepressant drug use did not appear to have
ing depression than the use of serotonin pre-
a well-documented antidepressant effect.24
cursors. Two 1980 case studies suggested L-
Authors of a 1983 review were not convinced
tyrosine may have potential as an antidepres-
of L-tryptophan’s antidepressant efficacy in
sant, but both had a very small sample size.27,28
marked-to-severe endogenous depression, but
Later in the 1980s, a four-week clinical trial
noted it might be more effective in moderate
treated 65 outpatients with major depression
in a double-blind comparison of L-tyrosine
serotonin-deficient subgroup of depressed
(100 mg/kg/day), imipramine, or placebo. It
found no evidence that L-tyrosine had antide-
stating, “results suggest that 5-HTP possesses
antidepressant properties, but additional trials
1979, DL-phenylalanine (150-200 mg/day) or
imipramine was administered to 40 depressed
patients (20 in each group) for one month. No
statistical difference was found between the
neurotransmitter precursor studies. Promising
results have been obtained in open studies and
Scale and a self-rating questionnaire,30 lead-
in comparisons with tricyclic antidepressants.
ing to a conclusion that DL-phenylalanine
In the open studies, however, some or all of
(DLPA) might have antidepressant properties.
might have been due to a placebo effect. Most
major depressive disorder were treated with
of the comparison studies also lacked a placebo
D-phenylalanine (mean dose of 350 mg/day)
control group, and the number of patients per
for four weeks. The researchers found no evi-
dence of antidepressant effect, but suggested
normally be necessary to show a statistically
Page 68 Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000
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re-evaluation at higher doses. 31 In a later open
serotonergic or catecholaminergic precursors.
study, 31 of 40 depressed patients responded
Studies which have investigated the ratio of
to large doses of L-phenylalanine (up to 14 g/
plasma tryptophan to the sum of the other large
neutral amino acids (leucine, isoleucine, va-
line, tyrosine, phenylalanine) or erythrocyte
membrane transport of these substances show
pramine, and the relatively low dose of DLPA
a predictable response to serotonergic or cat-
which was used, it seems higher doses might
echolaminergic precursors or drugs.33-35 This
be helpful in cases of depression in which low
type of testing might be one way of choosing
norepinephrine activity is involved.
between serotonin or catecholamine stimula-tion in the depressed patient.Conclusions
sors may be a reasonable course of action for
difficulty of drawing firm conclusions from the
treating many cases of depression, practitio-
research on the use of neurotransmitter pre-
ners should be aware that recent research on
cursors for treating depression. While there is
antidepressant drugs indicates they might have
undoubtedly evidence that precursor loading
a more complex and far-reaching action than
may be of therapeutic value, particularly for
that associated with neurotransmitter precur-
the serotonin precursors 5-HTP and L-tryp-
sors.6 In addition, if the intensive research into
tophan, more studies of suitable design and
development of faster acting antidepressant
size might lead to more conclusive results. In
drugs with fewer side-effects bears fruit, the
addition, the complex nature of neurotransmit-
advantages of neurotransmitter precursors in
ter systems contributes to uncertainty whether
terms of their better tolerability may be less
the positive response seen in studies of rela-
tively short duration would continue over the
respect to neurotransmitter precursors and pre-
scription antidepressant drugs is not necessar-
relevant the clinical research on neurotrans-
ily a case of “one or the other.” Growing num-
mitter precursors is for the types of depres-
bers of individuals are combining various pre-
sion alternative practitioners are likely to see.
scription drugs with alternative treatments, and
Nearly all of the studies have involved patients
the ranks of M.D.’s integrating alternative
with major depression, typically in a clinical
treatments into their practice is increasing.
setting. One reasonably large study of outpa-
Given this evolution, combined use of neu-
tients with mild or moderate depression found
rotransmitter precursors with antidepressant
L-tryptophan was significantly better than pla-
drugs may be worth considering. Nearly all of
cebo.22 This study is also noteworthy because
the studies of such use have been conducted
it followed the response of the subjects for a
with tricyclic drugs. A small study conducted
relatively long period (three months). Thus,
in 1986 found evidence of adverse effects from
in cases of mild or moderate depression, it does
combined administration of tryptophan and
not seem unreasonable to use neurotransmit-
Prozac.36 Yet it seems possible that use of low
ter precursors, especially given their relatively
dosages in combination might yield a positive
low degree of side-effects and low cost.
research is combining serotonergic and cat-
what limited guidance for choosing between
echolaminergic precursors. Two studies in theearly 1980s investigated a mixture of 5-HTP
Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000 Page 69
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and tyrosine in depression. While these stud-
Birdsall TC. 5-hydroxytryptophan: a clini-
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results indicate a tyrosine had a potentiatingeffect on the antidepressant capacity of 5-
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